The present invention provides potentiators of glutamate receptors (compounds of formula I), pharmaceutical compositions thereof, and methods of using the same, processes for preparing the same, and intermediates thereof.
The excitatory amino acid L-glutamate (sometimes referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS). The excitatory amino acids, including glutamate, are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ionic channels. Via activation of the iGlu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS. The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d glutamate (mGlu) receptor. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The present invention relates to potentiators of mGlu receptors. The mGlu receptors belong to the Type III G-protein coupled receptor (GPCR) superfamily. This superfamily of GPCR""s, including the calcium-sensing receptors, GABAB receptors and pheromone receptors, which are unique in that they are activated by binding of effectors to the amino-terminus portion of the receptor protein. The mGlu receptors are thought to mediate glutamate""s demonstrated ability to modulate intracellular signal transduction pathways. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). They have been demonstrated to be localized both pre- and post-synaptically where they can regulate neurotransmitter release, either glutamate or other neurotransmitters, or modify the post-synaptic response of neurotransmitters, respectively.
At present, there are eight distinct mGlu receptors that have been positively identified, cloned, and their sequences reported. These are further subdivided based on their amino acid sequence homology, their ability to effect certain signal transduction mechanisms, and their known pharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). For instance, the Group I mGlu receptors, which include the mGlu1 and mGlu5, are known to activate phospholipase C (PLC) via Gxcex1q-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization. There are several compounds that are reported to activate the Group I mGlu receptors including DHPG, (R/S)-3,5-dihydroxyphenylglycine. Schoepp, Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769 (1994); Ito, et al., Neurorep., 3, 1013 (1992). The Group II mGlu receptors consist of the two distinct receptors, mGlu2 and mGlu3 receptors. Both have been found to be negatively coupled to adenylate cyclase via activation of Gxcex1i-protein. These receptors can be activated by a group-selective compound such as 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, et al., J. Med. Chem., 40, 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997). Similarly, the Group III mGlu receptors, including mGlu4, mGlu6, mGlu7 and mGlu8, are negatively coupled to adenylate cyclase via Gxcex1i and are potently activated by L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24, 439 (1994).
It should be noted that many of the available pharmacological tools are not ideal in that they cross react not only on the receptors within a Group of mGlu receptors but also often have some activity between Groups of mGlu receptors. For instance, compounds such as 1S,3R-ACPD, (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, are believed to activate all of the Group I, II and III mGlu receptors depending upon the dose utilized while others, such as 1S,3S-ACPD, (1S, 3S)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, are more selective for the Group II receptors (mGlu2/3) than the Group I (mGlu1/5) or Group III (mGlu4/6/7/8). Schoepp, Neurochem. Int., 24, 439 (1994). To date, there are very few examples of selective agents for the mGlu receptors. Schoepp, Jane, and Monn, Neuropharmacol., 38, 1431 (1999).
It has become increasingly clear that there is a link between modulation of excitatory amino acid receptors, including the glutamatergic system, through changes in glutamate release or alteration in postsynaptic receptor activation, and a variety of neurological and psychiatric disorders. e.g. Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365-402 (1989); Schoepp and Sacann, Neurobio. Aging, 15, 261-263 (1994); Meldrum and Garthwaite, Tr. Pharmacol. Sci., 11, 379-387 (1990). The medical consequences of such glutamate dysfunction makes the abatement of these neurological processes an important therapeutic goal.
This invention provides compounds of formula I: 
wherein
R1 is selected from the group consisting of xe2x80x94C(O)R3, xe2x80x94C(O)OR4, and xe2x80x94SO2R5 
xe2x80x83wherein R3 is selected from the group consisting of alkyl and cycloalkyl, R4 is selected from the group consisting of alkyl and cycloalkyl, R5 is selected from the group consisting of alkyl, cycloalkyl, and fluorinated alkyl;
R2 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, hydroxy, trisubstituted silyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkyl, substituted cycloalkyl, halogen, cyano, nitro, phenyl, substituted phenyl, pyridyloxy, thiophenoxy, substituted thiophenoxy, phenylsulfinyl, substituted phenylsulfinyl, phenylsulfonyl, substituted phenylsulfonyl, benzoyl, substituted benzoyl, phenoxy, and substituted phenoxy;
or
two R2 substituents are taken together, on adjacent positions, to form a fused cycloalkyl or a methylenedioxy ring, and one R2 substituent is selected from the group consisting of hydrogen, hydroxy, trisubstituted silyloxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkyl, substituted cycloalkyl, halogen, cyano, nitro, phenyl, substituted phenyl, pyridyloxy, thiophenoxy, substituted thiophenoxy, phenylsulfinyl, substituted phenylsulfinyl, phenylsulfonyl, substituted phenylsulfonyl, benzoyl, substituted benzoyl, phenoxy, and substituted phenoxy;
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, alkyl, alkoxy, trifluoromethyl, halogen, phenoxy, and substituted phenoxy;
X is selected from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHR7xe2x80x94, and xe2x80x94CH2CH2xe2x80x94 wherein R7 is lower alkyl;
Y is selected from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CHR9CH2xe2x80x94, and xe2x80x94CH2CHR9 wherein R8 is lower alkyl and R9 is lower alkyl;
and the pharmaceutically acceptable salts thereof and the pyridyl N-oxide thereof.
The present invention also provides for novel pharmaceutical compositions, comprising: a compound of the formula I and a pharmaceutically acceptable diluent.
Because the compounds of formula I enhance the normal physiological function of the mGlu receptors, the compounds of formula I are useful for the treatment of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer""s disease, Huntington""s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson""s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders-(including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, and conduct disorder.
In another embodiment the present invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. That is, the present invention provides for the use of a compound of formula I or pharmaceutical composition thereof for the treatment neurological and psychiatric disorders associated with glutamate dysfunction.
Of the disorders above, the treatment of migraine, anxiety, schizophrenia, and epilepsy are of particular importance.
In a preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
In another preferred embodiment the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder.
In another preferred embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
In yet another preferred embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
In another embodiment of the present invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising: administering to a patient in need thereof an effective amount of a potentiator of metabotropic glutamate receptors.
Specifically, the present invention provides a method of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising: administering to a patient in need thereof an effective amount of a potentiator of mGlu2 and/or mGlu3 receptors.
In a preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a metabotropic glutamate potentiator, in particular a potentiator of mGlu2 and/or mGlu3 receptors.
In another preferred embodiment the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a metabotropic glutamate potentiator, in particular a potentiator of mGlu2 and/or mGlu3 receptors.
Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder.
In another preferred embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a metabotropic glutamate potentiator, in particular a potentiator of mGlu2 and/or mGlu3 receptors.
In yet another preferred embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a metabotropic glutamate potentiator, in particular a potentiator of mGlu2 and/or mGlu3 receptors.
Because such potentiators, including the compounds of formula I, positively modulate metabotropic glutamate receptor response to glutamate, it is an advantage that the present methods utilize endogenous glutamate.
Because such potentiators positively modulate metabotropic glutamate receptor response to glutamate agonists it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administering an effective amount of a metabotropic glutamate potentiator, including the compounds of formula I, in combination with a potentiated amount of a metabotropic glutamate receptor agonist. Such a combination may be advantageous in that it may augment the activity and selectivity of an agonist of metabotropic glutamate receptors, in particular a potentiator of mGlu2 and/or mGlu3 receptors.